tbuckley/cabot-search huggingface dataset:
Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer
Authors: Brittiny Dhital, Sandra Santasusagna, Perumalraja Kirthika, Michael Xu, Peiyao Li, Marc Carceles-Cordon, Rajesh K. Soni, Zhuoning Li, Ronald C. Hendrickson, Matthew J. Schiewer, William K. Kelly, Cora N. Sternberg, Jun Luo, Amaia Lujambio, Carlos Cordon-Cardo, Monica Alvarez-Fernandez, Marcos Malumbres, Haojie Huang, Adam Ertel, Josep Domingo-Domenech, Veronica Rodriguez-Bravo
Journal: Cell Reports Medicine (2023)

Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa.
JAMA Neurology
Journal: JAMA Neurology (2023)

The mission of JAMA Neurology is to publish and disseminate scientific information primarily important for physicians caring for people with neurologic disorders and for those interested in the structure and function of the normal and diseased human nervous system.The specifi c aims are to (1) publish timely original research, including clinical trials that will directly improve clinical neurologic care and that will inform efforts to improve neurological health and promote health care equity; (2) report translational research that is pertinent to the understanding of neurologic disease; (3) address topics of practice, ethics, education, and public health that are a key part of modern medicine; and (4) provide a forum for discussion and publication of important topics including bias, racism, and diversity.This information will be published only after extensive review by scientifi c peers and journal editors so that clarity, rigor, originality, and precision are ensured.
CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance
Authors: Monique B Nilsson, Yan Yang, Simon Heeke, Sonia A Patel, Alissa Poteete, Hibiki Udagawa, Yasir Y Elamin, Cesar A Moran, Yukie Kashima, Thiruvengadam Arumugam, Xiaoxing Yu, Xiaoyang Ren, Lixia Diao, Li Shen, Qi Wang, Minying Zhang, Jacqulyne P Robichaux, Chunhua Shi, Allyson N Pfeil, Hai Tran, Don L Gibbons, Jason Bock, Jing Wang, John D Minna, Susumu S Kobayashi, Xiuning Le, John V Heymach
Journal: Cancer Cell (2023)
Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity
Authors: Evan C. Rosenberg, Simon Chamberland, Michael Bazelot, Erica R. Nebet, Xiaohan Wang, Sam McKenzie, Swati Jain, Stuart Greenhill, Max Wilson, Nicole Marley, Alejandro Salah, Shanice Bailey, Pabitra Hriday Patra, Rebecca Rose, Nicolas Chenouard, Simón(e) D. Sun, Drew Jones, György Buzsáki, Orrin Devinsky, Gavin Woodhall, Helen E. Scharfman, Benjamin J. Whalley, Richard W. Tsien
Journal: Neuron (2023)

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI's pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI's synaptic effects and dampening hyperexcitability.
First <i>in vivo</i> fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod
Authors: Ludger Starke, Jason M. Millward, Christian Prinz, Fatima Sherazi, Helmar Waiczies, Christoph Lippert, Marc Nazaré, Friedemann Paul, Thoralf Niendorf, Sonia Waiczies
Journal: Theranostics (2023)

Theranostic imaging methods could greatly enhance our understanding of the distribution of CNS-acting drugs in individual patients.Fluorine-19 magnetic resonance imaging ( 19 F MRI) offers the opportunity to localize and quantify fluorinated drugs non-invasively, without modifications and without the application of ionizing or other harmful radiation.Here we investigated siponimod, a sphingosine 1-phosphate (S1P) receptor antagonist indicated for secondary progressive multiple sclerosis (SPMS), to determine the feasibility of in vivo 19 F MR imaging of a disease modifying drug.Methods: The 19 F MR properties of siponimod were characterized using spectroscopic techniques.Four MRI methods were investigated to determine which was the most sensitive for 19 F MR imaging of siponimod under biological conditions.We subsequently administered siponimod orally to 6 mice and acquired 19 F MR spectra and images in vivo directly after administration, and in ex vivo tissues.Results: The 19 F transverse relaxation time of siponimod was 381 ms when dissolved in dimethyl sulfoxide, and substantially reduced to 5 ms when combined with serum, and to 20 ms in ex vivo liver tissue.Ultrashort echo time (UTE) imaging was determined to be the most sensitive MRI technique for imaging siponimod in a biological context and was used to map the drug in vivo in the stomach and liver.Ex vivo images in the liver and brain showed an inhomogeneous distribution of siponimod in both organs.In the brain, siponimod accumulated predominantly in the cerebrum but not the cerebellum.No secondary 19 F signals were detected from metabolites.From a translational perspective, we found that acquisitions done on a 3.0 T clinical MR scanner were 2.75 times more sensitive than acquisitions performed on a preclinical 9.4 T MR setup when taking changes in brain size across species into consideration and using equivalent relative spatial resolution.Conclusion: Siponimod can be imaged non-invasively using 19 F UTE MRI in the form administered to MS patients, without modification.This study lays the groundwork for more extensive preclinical and clinical investigations.With the necessary technical development, 19 F MRI has the potential to become a powerful theranostic tool for studying the time-course and distribution of CNS-acting drugs within the brain, especially during pathology.
Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety
Authors: Alec J. Batts, Robin Ji, Rebecca L. Noel, Alina R. Kline-Schoder, Sua Bae, Nancy Kwon, Elisa E. Konofagou
Journal: Theranostics (2023)

Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL. The RASTA sequence was further employed to evaluate the impact of USPL on BBB opening volume, power cavitation imaging (PCI) pixel intensity, BBB closing timeline, drug delivery efficiency, and safety. Methods: A P4-1 phased array transducer driven by a Verasonics Vantage ultrasound system was operated using a custom script to run the RASTA sequence which consisted of interleaved steered, focused transmits and passive imaging. Contrast-enhanced magnetic resonance imaging (MRI) confirmed initial opening volume and closure of the BBB by longitudinal imaging through 72 hours post-BBB opening. For drug delivery experiments, mice were systemically administered a 70 kDa fluorescent dextran or adeno-associated virus serotype 9 (AAV9) for fluorescence microscopy or enzyme-linked immunosorbent assay (ELISA) to evaluate ThUS-mediated molecular therapeutic delivery. Additional brain sections were also H&E-stained to evaluate histological damage, and IBA1- and GFAP-stained to elucidate the effects of ThUS-mediated BBB opening on stimulation of key cell types involved in the neuro-immune response, microglia and astrocytes. Results: The ThUS RASTA sequence induced distinct BBB openings simultaneously in the same mouse where volume, PCI pixel intensity, level of dextran delivery, and AAV reporter transgene expression were correlated with brain hemisphere-specific USPL, consistent with statistically significant differences between 1.5, 5, and 10-cycle USPL groups. BBB closure after ThUS required 2-48 hours depending on USPL. The potential for acute damage and neuro-immune activation increased with USPL, but such observable damage was nearly reversed 96 hours post-ThUS. Conclusion: ThUS is a versatile single-array technique which exhibits the potential for investigating a variety of non-invasive therapeutic delivery applications in the brain.
Colonization with two different <i>Blastocystis</i> subtypes in DSS-induced colitis mice is associated with strikingly different microbiome and pathological features
Authors: Lei Deng, Lukasz Wojciech, Chin Wen Png, Dorinda Yan Qin Kioh, Yuxiang Gu, Thet Tun Aung, Benoit Malleret, Eric Chun Yong Chan, Guangneng Peng, Yongliang Zhang, Nicholas Robert John Gascoigne, Kevin Shyong Wei Tan
Journal: Theranostics (2023)

Rationale:The gut microbiota plays a significant role in the pathogenesis of inflammatory bowel disease (IBD).However, the role of Blastocystis infection and Blastocystis-altered gut microbiota in the development of inflammatory diseases and their underlying mechanisms are not well understood.Methods: We investigated the effect of Blastocystis ST4 and ST7 infection on the intestinal microbiota, metabolism, and host immune responses, and then explored the role of Blastocystis-altered gut microbiome in the development of dextran sulfate sodium (DSS)-induced colitis in mice.Results: This study showed that prior colonization with ST4 conferred protection from DSS-induced colitis through elevating the abundance of beneficial bacteria, short-chain fatty acid (SCFA) production and the proportion of Foxp3 + and IL-10-producing CD4 + T cells.Conversely, prior ST7 infection exacerbated the severity of colitis by increasing the proportion of pathogenic bacteria and inducing pro-inflammatory IL-17A and TNF-α-producing CD4 + T cells.Furthermore, transplantation of ST4-and ST7-altered microbiota resulted in similar phenotypes.Conclusions: Our data showed that ST4 and ST7 infection exert strikingly differential effects on the gut microbiota, and these could influence the susceptibility to colitis.ST4 colonization prevented DSS-induced colitis in mice and may be considered as a novel therapeutic strategy against immunological diseases in the future, while ST7 infection is a potential risk factor for the development of experimentally induced colitis that warrants attention.
Combined use of magnetic microbeads for endothelial cell isolation and enhanced cell engraftment in myocardial repair
Authors: Christian Biederbick, Jan C Heinemann, Sarah Rieck, Florian Winkler, Annika Ottersbach, Miriam Schiffer, Georg D Duerr, Dietmar Eberbeck, Michael Hesse, Wilhelm Röll, Daniela Wenzel
Journal: Theranostics (2023)

Background: The regenerative potential of the heart after injury is limited. Therefore, cell replacement strategies have been developed. However, the engraftment of transplanted cells in the myocardium is very inefficient. In addition, the use of heterogeneous cell populations precludes the reproducibility of the outcome. Methods: To address both issues, in this proof of principle study, we applied magnetic microbeads for combined isolation of eGFP+ embryonic cardiac endothelial cells (CECs) by antigen-specific magnet-associated cell sorting (MACS) and improved engraftment of these cells in myocardial infarction by magnetic fields. Results: MACS provided CECs of high purity decorated with magnetic microbeads. In vitro experiments revealed that the angiogenic potential of microbead-labeled CECs was preserved and the magnetic moment of the cells was strong enough for site-specific positioning by a magnetic field. After myocardial infarction in mice, intramyocardial CEC injection in the presence of a magnet resulted in a strong improvement of cell engraftment and eGFP+ vascular network formation in the hearts. Hemodynamic and morphometric analysis demonstrated augmented heart function and reduced infarct size only when a magnetic field was applied. Conclusion: Thus, the combined use of magnetic microbeads for cell isolation and enhanced cell engraftment in the presence of a magnetic field is a powerful approach to improve cell transplantation strategies in the heart.
Transcriptional Downregulation of miR-4306 serves as a New Therapeutic Target for Triple Negative Breast Cancer: Erratum
Authors: Zitong Zhao, Lin Li, Peina Du, Liying Ma, Weimin Zhang, Leilei Zheng, Bo Lan, Bailin Zhang, Fei Ma, Bo Xu, Qimin Zhan, Yongmei Song
Journal: Theranostics (2023)

[This corrects the article DOI: 10.7150/thno.30701.].
Proteomes from AMPK-inhibited peripheral blood mononuclear cells suppress the progression of breast cancer and bone metastasis
Authors: Kexin Li, Xun Sun, Kazumasa Minami, Keisuke Tamari, Kazuhiko Ogawa, Hudie Li, Hailan Ma, Meng Zhou, Sungsoo Na, Bai-Yan Li, Hiroki Yokota
Journal: Theranostics (2023)

Background: During a developmental process, embryos employ varying tactics to remove unwanted cells.Using a procedure analogous to some of the embryonic cells, we generated a tumor-eliminating conditioned medium (CM) from AMPK-inhibited lymphocytes and monocytes in peripheral blood mononuclear cells (PBMCs).Methods: AMPK signaling was inhibited by the application of a pharmacological agent, Dorsomorphin, and the therapeutic effects of their conditioned medium (CM) were evaluated using in vitro cell cultures, ex vivo breast cancer tissues, and a mouse model of mammary tumors and tumor-induced osteolysis.The regulatory mechanism was evaluated using mass spectrometry-based proteomics, Western blotting, immunoprecipitation, gene overexpression, and RNA interference.Results: While AMPK signaling acted mostly anti-tumorigenic, we paradoxically inhibited it to build induced tumor-suppressing cells and their tumor-eliminating CM.In a mouse model of breast cancer, the application of AMPK-inhibited lymphocyte-derived CM reduced mammary tumors additively to a chemotherapeutic agent, Taxol.It also prevented bone loss in the tumor-bearing tibia.Furthermore, the application of CM from the patient-derived peripheral blood diminished ex vivo breast cancer tissues isolated from the same patients.Notably, proteins enriched in CM included Moesin (MSN), Enolase 1 (ENO1), and polyA-binding protein 1 (PABPC1), which are considered tumorigenic in many types of cancer.The tumor-suppressing actions of MSN and ENO1 were at least in part mediated by Metadherin (Mtdh), which is known to promote metastatic seeding. Conclusion:We demonstrated that PBMCs can be used to generate tumor-suppressive proteomes, and extracellular tumor-suppressing proteins such as MSN, ENO1, and PABPC1 are converted from tumor-promoting factors inside cancer cells.The results support the possibility of developing autologous blood-based therapy, in which tumor-suppressing proteins are enriched in engineered PBMC-derived CM by the inhibition of AMPK signaling.
PLK1-mediated phosphorylation of β-catenin enhances its stability and transcriptional activity for extracellular matrix remodeling in metastatic NSCLC
Authors: Da-Eun Kim, Sol-Bi Shin, Chang-Hyeon Kim, Yeo-Bin Kim, Hyun-Ji Oh, Hyungshin Yim
Journal: Theranostics (2023)

Rationale: β-catenin is a component for cell adhesion and a transcriptional coactivator in epithelial-mesenchymal transition (EMT). Previously we found that catalytically active PLK1 drives EMT in non-small cell lung cancer (NSCLC), upregulating extracellular matrix factors including TSG6, laminin γ2, and CD44. To understand the underlying mechanism and clinical significance of PLK1 and β-catenin in NSCLC, their relationship and function in metastatic regulation were investigated. Methods: The clinical relevance between the survival rate of NSCLC patients and the expression of PLK1 and β-catenin was analyzed by a KM plot. Immunoprecipitation, kinase assay, LC-MS/MS spectrometry, and site-directed mutagenesis were performed to reveal their interaction and phosphorylation. A lentiviral doxycycline-inducible system, Transwell-based 3D culture, tail-vein injection model, confocal microscopy, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated β-catenin in the EMT of NSCLC. Results: Clinical analysis revealed that the high expression of CTNNB1/PLK1 was inversely correlated with the survival rates of 1,292 NSCLC patients, especially in metastatic NSCLC. In TGF-β-induced or active PLK1-driven EMT, β-catenin, PLK1, TSG6, laminin γ2, and CD44 were concurrently upregulated. β-catenin is a binding partner of PLK1 in TGF-β-induced EMT and is phosphorylated at S311. Phosphomimetic β-catenin promotes cell motility, invasiveness of NSCLC cells, and metastasis in a tail-vein injection mouse model. Its upregulated stability by phosphorylation enhances transcriptional activity through nuclear translocation for the expression of laminin γ2, CD44, and c-Jun, therefore enhancing PLK1 expression by AP-1. Conclusions: Our findings provide evidence for the critical role of the PLK1/β-catenin/AP-1 axis in metastatic NSCLC, implying that β-catenin and PLK1 may serve as a molecular target and prognostic indicator of the therapeutic response in metastatic NSCLC patients.
Human circulating small non-coding RNA signature as a non-invasive biomarker in clinical diagnosis of acute myeloid leukaemia
Authors: Lin Xia, Huanping Guo, Xiao Wu, Yinying Xu, Pan Zhao, Bingbing Yan, Yunjing Zeng, Yundi He, Dan Chen, Robert Peter Gale, Yunfang Zhang, Xi Zhang
Journal: Theranostics (2023)

Background: Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults; AML is highly heterogeneous and involves abnormalities at multiple omics levels.Small non-coding RNAs (sncRNAs) present in body fluids are important regulatory molecules and considered promising non-invasive clinical diagnostic biomarkers for disease.However, the signature of sncRNA profile alteration in AML patient serum and bone marrow supernatant is still under exploration.Methods: We examined data for blood and bone marrow samples from 80 consecutive, newly-diagnosed patients with AML and 12 healthy controls for high throughput small RNA-sequencing.Differentially expressed sncRNAs were analysed to reveal distinct patterns between AML patients and controls.Machine learning methods were used to evaluate the efficiency of specific sncRNAs in discriminating individuals with AML from controls.The altered expression level of individual sncRNAs was evaluated by RT-PCR, Q-PCR, and northern blot.Correlation analysis was employed to assess sncRNA patterns between serum and bone marrow supernatant. Results:We identified over 20 types of sncRNA categories beyond miRNAs in both serum and bone marrow supernatant, with highly coordinated expression patterns between them.Non-classical sncRNAs, including rsRNA (62.86%), ysRNA (14.97%), and tsRNA (4.22%), dominated among serum sncRNAs and showed sensitive alteration patterns in AML patients.According to machine learning-based algorithms, the tsRNA-based signature robustly discriminated subjects with AML from controls and was more reliable than that comprising miRNAs.Our data also showed that serum tsRNAs to be closely associated with AML prognosis, suggesting the potential application of serum tsRNAs as biomarkers to assist in AML diagnosis.Conclusions: We comprehensively characterized the expression pattern of circulating sncRNAs in blood and bone marrow and their alteration signature between healthy controls and AML patients.This study enriches research of sncRNAs in the regulation of AML, and provides insights into the role of sncRNAs in AML.
GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT
Authors: Frédéric Baron, Myriam Labopin, Johanna Tischer, Anna Maria Raiola, Jan Vydra, Didier Blaise, Patrizia Chiusolo, Friedrich Stölzel, Renato Fanin, Patrice Chevallier, Arnon Nagler, Fabio Ciceri, Mohamad Mohty
Journal: Journal of Hematology & Oncology (2023)

Abstract The association between graft-versus-host disease (GVHD) occurrence and acute myeloid leukemia (AML) relapse in patients treated with HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis has remained debated. Here, we addressed this issue in patients with active AML at transplantation. 2-year cumulative incidences of relapse and leukemia-free survival (LFS) were 49% and 32.3%, respectively. There were no associations between acute nor chronic GVHD of any grade and lower relapse incidence. However, grade I acute GVHD was associated with better LFS (HR = 0.71, 95% CI 0.51–0.99, P = 0.04). In contrast, grade III–IV acute (HR = 3.09, 95% CI 1.87–5.12, P &lt; 0.0001) as well as extensive chronic (HR = 3.3, 95% CI 1.81–6.04, P = 0.0001) GVHD correlated with higher nonrelapse mortality leading to lower LFS (HR = 1.36, 95% CI 0.99–1.86, P = 0.056 and HR = 1.97, 95% CI 1.35–2.89, P = 0.0004, respectively). In conclusion, these data suggest a dissociation of graft-versus-leukemia effects from GVHD in patients with active AML treated with PTCy-based Haplo-HCT.